Fluoride-Releasing Compositions

ABSTRACT

Chelating monomers and fluoride-releasing compositions are disclosed that may be incorporated into dental composite restorative materials, dental bonding agents or other dental materials, to produce materials with high fluoride release rates, and high fluoride recharge capability. Such dental restorative materials may help reduce the level of dental caries in patients, particularly the level of caries occurring on the margins of the restorative materials.

This is a continuation of application Ser. No. 13/483,624, filed May 30,2012, now allowed with the issue fee paid; which is a divisional ofapplication Ser. No. 12/526,321, 35 U.S.C. §371 completion date Sep. 2,2009, now U.S. Pat. No. 8,217,173; which is the national stage ofinternational application PCT/US2008/053683, international filing dateFeb. 12, 2008; which claims the benefit of the Feb. 13, 2007 filing dateof provisional patent application 60/889,653 under 35 U.S.C. §119(e);the complete disclosures of all of which are hereby incorporated byreference in their entirety.

The development of this invention was funded by the Government undergrant number 1P20RR020160 awarded by the National Institutes of Health,Center of Biomedical Research Excellence. The Government has certainrights in this invention.

This invention pertains to compositions that release fluoride ion andthat may be readily recharged with additional fluoride ion. Thesecompositions are useful, for example, in dental composites, dentalbonding agents, and other resin-based dental materials.

Fluoride is the most widely used agent to prevent dental caries (toothdecay). Tooth decay can occur on the margins of dental restorations.Such recurring or secondary caries is a frequent cause for failure ofdental restorations. Fluoride-releasing restorative materials have beenused to try to reduce recurrent caries at restoration margins. Theeffectiveness of such fluoride-releasing materials varies widely.Fluoride-releasing materials generally fall into one of four categories:glass ionomers, resin-modified glass ionomers, polyacid-modifiedcomposite resins (so-called “compomers”) and fluoride-releasingcomposite resins. In general, materials with higher levels of fluoriderelease have tended to have poorer mechanical properties (e.g., a lowercompressive strength). High fluoride-releasing materials (glass ionomersand resin-modified glass ionomers) have therefore been used clinicallyprimarily to restore decayed, but non-biting areas.

Composite resins have been widely used in restorative dentistry becausethey have high strength, good wear resistance, and excellent esthetics,but they release relatively small amounts of fluoride, and have lowfluoride-recharge capacity. There is an unfilled need for dentalcomposite resins with high strength, good wear resistance, high fluoriderelease rates, and high fluoride recharge capability, i.e., the abilityto take up fluoride from an aqueous solution containing a highconcentration of fluoride (e.g., a fluoridated toothpaste, topicalfluoride agent, or mouthwash).

Composite resins require bonding agents to bond to tooth structure.Current dental bonding agents have little fluoride-releasing andrecharging capabilities and form a barrier hindering the transport offluoride from the restorative materials into the tooth structures.Sealants, which are resins with or without fillers, have been used tofill the pits and fissures in posterior teeth, but many dentists arereluctant to use sealants because they fear that caries in sealedcarious pits or fissures may progress. Thus there is an unfilled needfor dental bonding agents and sealants that have excellent adhesion totooth structures, high fluoride release rates, and high fluoriderecharge capability.

Currently, fluoride released from resin-based dental restorativematerials comes from four main sources: (1) a soluble free salt, such asNaF, KF, or SnF₂ added to the material; (2) fluoride-releasing glassfillers such as fluoroaluminosilicate glass, or sparingly solubleinorganic salts such as YbF₃; (3) polymer molecules containing ananion-exchangeable fluoride moiety such as —N(CH₃)₂HF; or (4) organicfluoride sources such as those from alkylonium tetrafluoroborate.

U.S. Pat. No. 6,391,286 discloses fluoride releasing materials for usein dental compositions, having the formula M(G)_(g)(F)_(n) orM(G)_(g)(ZF_(m))_(n), where M is an element capable of forming acationic species and having a valence of 2 or more; G is an organicchelating moiety capable of complexing with the element M; Z ishydrogen, boron, nitrogen, phosphorus, sulfur, antimony, or arsenic; Fis fluoride; and g, m, and n are each at least 1.

U.S. Pat. No. 4,871,786 discloses dental compositions employing one ormore substantially soluble organic compounds that serve as fluoridesources by incorporating tetrafluoroborate. Preferred non-polymerizablefluoride sources were said to be compounds of the formula: R_(n)-M⁺ BF₄⁻ where M is I, N, P, or S; n is 2, 3, or 4, depending on the identityof M; and R is one of several specified types of substituted orunsubstituted hydrocarbon chains. Preferred polymerizable fluoridesources were said to be compounds of the formula: R_((n−1)))-M⁺(L) BF₄ ⁻where the other symbols were as previous stated, and L is an organicligand comprising a moiety capable of polymerization via a cationic,condensation, or free radical mechanism.

U.S. Pat. No. 6,703,518 discloses fluoride releasing compositionscomprising chelating monomers and ternary metal fluoride chelates. Forexample, the chelating monomers may contain chelating groups ofaminodiacetic acids, amidodiacetic acids, or phosphonic acids. Thechelating monomers may also include short-chain monomers containingvinylbenzyl, methacrylate, or bis(carboxymethyl)-L-lysine.

Published international patent application WO 00/69394 discloses whatwere said to be stable dental materials comprising a compound havingonly one acid functionality and at least one polymerizablefunctionality. The material does not contain deleterious quantities ofpolyacid compounds. The material also contains a fluoride sourcecontaining polyvalent metal ions, and a photopolymerization initiator.

A. Yuchi et al., “Complexes of Hard Metal Ions withAmine-N-Polycarboxylates as Fluoride Receptors,” Bull. Chem. Soc. Jpn.,vol. 69, pp. 3173-3177 (1996) discloses studies of equilibria in thereaction of hard metal complexes (M^(m+):Al³⁺, Zr⁴⁺, Hf⁴⁺, Th⁴⁺; H_(n)L:amine-N-polycarboxylic acid) with fluoride. The zirconium (IV) complexof N-methyliminodiacetic acid was reported to be an excellent fluoridereceptor.

M. Chikuma et al., “Selective Sorption of Fluoride Ions byAnion-Exchange Resin Modified with Alizarin Fluorine Blue-Praseodymium(III) Complex,” Reactive Polymers, vol. 13, pp. 131-138 (1990) disclosesa resin for the selective sorption of fluoride ion, prepared from ananion exchange resin, Amberlite™ IRA 400, and a praseodymium (III)complex of alizarin fluorine blue.

H. Rawls et al., “Esthetic Materials with Active Agent Control ReleaseCapabilities and Their Future Roles,” pp. 130-135 in Symposium onEsthetic Restorative Materials, 1991 (American Dental Association 1993)provides a review of dual-purpose dental restorative materials: thosethat can both serve the needs of esthetic dentistry and that can alsoserve as sustained-release sources of therapeutic agents, such asfluoride. See also H. Rawls, “Preventive Dental Materials: SustainedDelivery of Fluoride and Other Therapeutic Agents,” Advances in DentalResearch, vol. 5, pp. 50-55 (December 1991).

E. Glasspoole et al., “A Fluoride-Releasing Composite for DentalApplications,” Dental Materials, vol. 17, pp. 127-133 (2001) disclosesthe incorporation of an organic fluoride material, tetrabutylammoniumtetrafluoroborate, into a hydrophilic monomer system made of2,2-bis[4-(2-hydroxy-3-methacroyloxypropoxy)phenyl]-propane and2-hydroxyethyl methacrylate. The resulting fluoride release rates werereported to exceed those of several glass ionomer materials that werealso tested.

B. Zimmerman et al., “Prevention of in vitro Secondary Caries with anExperimental Fluoride-Exchanging Restorative Resin,” J. Dental Res.,vol. 63, pp. 689-692 (1984) reported clinical observations in whichexperimental composite resins that released fluoride by ion exchangewere seen to reduce the incidence of caries in immediately adjacentareas, as compared to the rates of caries observed whennon-fluoride-containing materials were used.

Several publications by one or more of the present inventors havereported the synthesis of the fluoride-releasing dimethacrylate monomerscontaining aminodiacetic acids or amidodiacetic acids and theirapplications in fluoride-releasing dental composites. See X. Xu et al.,“Synthesis and Characterization of a Novel, Fluoride-ReleasingDimethacrylate Monomer and Its Dental Composite” Journal of PolymerScience: Part A: Polymer Chemistry, 2004; 42:985-995; X. Xu et al.,“Synthesis and Characterization of Novel Fluoride-Releasing Monomers 2:Dimethacrylates Containing Bis(aminodiacetic acid) and Their TernaryZirconium-Fluoride Complexes,” Journal of Polymer Science A: PolymerChemistry 2005, 43, 3135-3166; X. Xu et al., “Formulation andcharacterization of a novel fluoride-releasing dental composite,” DentalMaterials 2006, 22(11): 1014-1023. While these previously-reportedcompositions are useful, there is still a need for compositions withenhanced stabilities and fluoride recharge capabilities.

Hydroxypyridinones (HOPO), which have adjacent keto and hydroxyl groups,and catechols, which have two adjacent hydroxyl groups, are bothbidentate chelating ligands. They can form five-member rings with heavymetals such as Fe (III) and Pu (IV). Multidentate chelating ligandscontaining two to four HOPO or catechol groups can form highly stablecomplexes with heavy metals. D. L. White et al., “Synthesis and initialbiological testing of polydentate oxohydroxy-pyridine-carboxylateligands,” J. Med. Chem. 1988, 31, 11-18, reported the synthesis ofwater-soluble chelating ligands containing two to four1,2-hydroxypyridinone (1,2-HOPO) groups. L. C. Uhlir et al., “Specificsequestering agents for the actinides. 21. Synthesis and initialbiological testing of octadentate mixed catecholate-hydroxypyridinonateligands,” J. Med. Chem. 1993, 36, 504-509, reported the synthesis ofmixed catecholate-hydroxypyridinonate ligands and their complexes withPu (IV). The high binding ability of these ligands for heavy metalsallows them to be used to remove actinides such as Pu(IV) frombiological systems.

M. Streater et al., “Novel 3-hydroxy-2 (1H)-pyridinones. Synthesis, Iron(III)-chelating properties, and biological activity,” J. Med. Chem.1990, 33, 1749-55, and K. N. Raymond et al., “3-hydroxy-2(1H)-pyridinonechelating agents,” U.S. Pat. No. 5,624,901, reported the synthesis ofchelating ligands containing 3-hydroxy-2(1H)-pyridinones (2,3-HOPO). J.Xu et al., “Synthesis and Initial Evaluation for In Vivo Chelation ofPu(IV) of a Mixed Octadentate Spermine-Based Ligand Containing4-Carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone and6-Carbamoyl-1-hydroxy-2(1H)-pyridinone,” J. Med. Chem. 2002, 45,3963-3971, reported the synthesis of chelating ligands containing4-Carbamoyl-3-hydroxy-1-methyl-2(1H)-pyridinone and6-Carbamoyl-1-hydroxy-2(1H)-pyridinone. These chelating ligands wereeffective in removing excess Fe (III) from biological systems, withlittle toxicity.

S. Liu, U.S. Pat. No. 6,932,960 reported the synthesis andpharmaceutical applications of N-substituted 3-hydroxy-4-pyridinones. R.L. Bruening et al., U.S. Pat. Nos. 6,221,476 and 6,432,313, reportedhydrophilic polymer membranes containing hydroxypyridinones and theirapplication in removal of metal ions.

Molecules containing β-diketones, particularly aromatic tetraketoneswith two β-diketones connected by a benzene or pyridine, are strongchelating ligands and can form complexes with many metal ions. See D. E.Fenton et al., “Binuclear Complexes of Tetraketones,” Inorganica ChimicaActa, 1982, 58, 83-88.

Polymers with antimicrobial (mainly antibacterial and antifungal)activities, generally known as polymeric biocides or antimicrobialpolymers, have drawn interest in the fields of biomedical materials andmedical implants. See Kenawy E-R et al., The Chemistry and Applicationsof Antimicrobial Polymers: A State-of-the-Art Review. Biomacromolecules2007; 8(5):1359-1384. Common biocide moieties include quaternaryammonium, pyridinium, phosphonium, and sulfonium salts. The mechanism ofaction of the quaternary compounds may be direct cationic binding tocell wall components, leading to disruption of the cell wall membrane,and subsequently leakage of cell contents and cell death. To achievehigh antimicrobial efficacy, the quaternary salt preferably has at leastone long-chain alkyl or substituted alkyl group, and a relatively lowtendency to form an ion-pair with the counter ion.

One of the few antibacterial monomers that has been used in dentalmaterials to date is methacryloyloxydodecyl pyrimidinium bromide (MDPB).See Imazato S. et al., Incorporation of bacterial inhibitor into resincomposite. Journal of Dental Research 1994; 73:1437-1443, Imazato S, etal., Incorporation of antibacterial monomer MDPB into dentin primer.Journal of Dental Research 1997; 76:768-772. The bactericidal activityof the monomer and different dental materials (primer, bonding adhesive,and composite) containing MDPB against oral Streptococci have beenstudied. See Imazato S, et al., Antibacterial activity and bondingcharacteristics of an adhesive resin containing antibacterial monomerMDPB. Dent. Mater. 2003; 19:313-319, and Imazato S. Antibacterialproperties of resin composites and dentin bonding systems. Dent. Mater.2003; 19:449-457. MDPB has been reported to inhibit bacterial growth inuncured resins, in cured resins, and in bonding agents. To incorporateantibacterial activity in a self-etching bonding agent would be ofparticular clinical importance, because self-etching bonding agents haveusually had pH higher than about 2.0, and have not effectively killedacid-resistant bacteria. By contrast, a conventional phosphoric acid(37%) etching gel has pH of 0.8 and effectively kills most bacteria.MDPB has been used in a commercial self-etching bonding agent, ProtectBond™ (Kuraray, Japan).

To the inventors' knowledge, the use of fluoride exchange monomers incombination with antibacterial monomers in dental materials has notpreviously been reported.

We have discovered novel chelating monomers and ternary metal fluoridechelates (fluoride-releasing monomers). The chelating monomers containboth polymerizable groups and chelating groups, such asbis(carboxymethyl)-L-lysine, hydroxypyridinones, catechols, and aromaticβ-diketones. Hydroxypyridinones (HOPOs) and catechols are linked to oneanother, for example via ether or alkyl groups, to form multidentatechelating ligands. The novel chelating ligands are less hydrophilic thanthose containing amide-linked HOPO ligands. They typically form morestable ternary metal fluoride chelates than will monomers containingaminodiacetic acids or amidodiacetic acids. The novel chelating monomersand novel fluoride-releasing compositions may, for example, beincorporated into dental composite restorative materials, dental bondingagents, or other dental materials, to produce materials with highfluoride release rates and high fluoride recharge capability.

The new chelating and fluoride-releasing monomers of the presentinvention include those having the following general formulas, where theformula on the left depicts a chelating monomer, and that on the rightdepicts a monomer chelated to a metal atom, which in turn is coordinatedto one or more fluoride ions:

(R)_(i)(L)_(j) or (R)_(i)(L)_(j)(M)_(k)(F)_(l)(W(R′)_(p))_(q) or(R)_(i)(L)_(i)(M)_(k)(F)_(l)(M_(q)

wherein: R is a substituted or unsubstituted aliphatic or aromatic grouphaving 3 to 100 carbon atoms, and having at least one polymerizablegroup, the polymerizable group being preferably, but not necessarily,located in a terminal position; L is a substituted or unsubstitutedaliphatic or aromatic chelating group having 3 to 100 carbon atoms,which is a multidentate (at least a bidentate) ligand; M is a metal atomhaving a valence of +2 or higher; i, j, k, and l are positive integersfrom 1 to 4; F is a fluoride atom; W is a counter-ion to maintain theneutrality of the monomer; R′ is an optional substituted orunsubstituted aliphatic or aromatic group having 1 to 50 carbon atoms,and having at least one polymerizable group; and p and q are integersfrom 0 to 4. R′ may bind W through a covalent bond, a coordination bond,or ionic bonding.

Preferred embodiments of the invention include one or more of thefollowing options: (1) the use of multiple polymerizable terminal groupsin the R (or R′) moieties or multiple Rs each with at least onepolymerizable terminal group, for example di- or polymethacrylates, toform a cross-linked polymer matrix; (2) including long-chain aliphaticor aromatic groups (10 or more carbon atoms) in the R moieties to reducehydrophilicity (water sorption) and to increase miscibility with otherdental monomers; (3) linking hydroxypyridinones and catechols together,for example through ether or alkyl groups, to form multidentatechelating ligands, which will generally be less hydrophilic than thosecontaining amide-linked HOPO ligands, increasing miscibility with otherdental monomers; (4) employing chelating ligands with a total of 3 to 6“donor” oxygen atoms, wherein the ionized ligands have a nominal valenceof −3, −2, or −1, which allows the coordination of one or moreadditional fluoride ions or ion-pairs containing fluoride (e.g., FH,tetraalkylammonium fluoride, etc.); (5) employing quaternary ammonium,pyridinium, phosphonium, or sulfonium cations, to serve both ascounter-ions and as antimicrobial agents.

In the general formula above, M is a metal having a valence of +2 orgreater. Preferred metals M are those having +3 or +4 valences,particularly those that tend to form colorless complexes with theligands and with fluoride. For example, M may be Sn⁺², Zn⁺², Sr⁺², Al⁺³,La⁺³, Ce⁺³, Sb⁺³, Yb⁺³, Ti⁺⁴, Sn⁺⁴, Zr⁺⁴, Ce⁺⁴, or Th⁺⁴. Particularlypreferred is Zr⁺⁴, because that cation is nontoxic, colorless, andrelatively inexpensive, has a high valence, and has a high tendency toform multinucleate complexes with fluoride ions, leading to highfluoride-exchange capacity. In addition, Zr has a high atomic weight,providing radio-opacity, a desirable property for dental restorativematerials.

W or W(R′)_(p) is a counter-ion to maintain the neutrality of themonomer, for example hydrogen, lithium, sodium, potassium, ammonium,quaternary ammonium, or pyridinium ions. Preferred R′ groups contain atleast one long-chain (at least 8 carbon atoms) alkyl or substitutedalkyl group with antimicrobial activity, more preferably with at leasttwo short-chain substituents (e.g., methyl) to reduce any tendency toform tight ion-pairs with fluoride ion. Preferred W(R′)_(p) include thefollowing examples:

The R and R′ groups in the general formula contain at least onepolymerizable moiety such as a C═C double bond, an epoxy group, anethyleneimine group, isocyanides, or thiol. Preferred R groups includethe esters of acrylic or methacrylic acid, for example methyl acrylate,methyl methacrylate, ethyl acrylate, ethyl methacrylate, propylacrylate, propyl methacrylate, isopropyl acrylate, isopropylmethacrylate, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate,hydroxypropyl acrylate, hydroxypropyl methacrylate, tetrahydrofurfurylacrylate, tetrahydrofurfuryl methacrylate, glycidyl acrylate, glycidylmethacrylate, glycerol mono- and diacrylate, glycerol mono- anddi-methacrylate, ethyleneglycol diacrylate, ethyleneglycoldimethacrylate, neopentyl glycol diacrylate, neopentylglycoldimethacrylate, and trimethylolpropane triacrylate.

Other examples of R or R′ include vinyl azalactone, vinyl pyrrolidone,styrene, divinylbenzene, urethane acrylates or methacrylates, epoxyacrylates or methacrylates and polyol acrylates or methacrylates,substituted acryl amides and methacrylamides.

Alternatively, the polymerizable component may be a cationically curablematerial, such as one of the epoxies, oxetanes, oxolanes, cyclicacetals, lactams, lactones, vinyl ethers, and spirocyclic compoundscontaining one or more oxygen atoms in the ring.

Particularly preferred examples of the R group include one or more ofthe following structures R1-R13:

wherein a dotted line represents the bond between R and a chelatinggroup L; X is an ether oxygen or an NH group; Z is hydrogen or asubstituted or unsubstituted alkyl group having from 1 to 12 carbonatoms such as methyl, ethyl, propyl, isopropyl, n-butyl, or t-butyl; Yis a pendent group that may or may not participate in chelate formation.The simplest Y is hydrogen, which does not ordinarily participate inchelate formation; and a typical Y is a hydroxyl group, which canparticipate in chelation. Y may also be, for example, an ester of aphosphoric acid, or a half ester of an aliphatic or aromatic diacid ortriacid having from 2 to 12 carbon atoms, such as oxalic acid, malonicacid, maleic acid, a mono- or disubstituted maleic acid, malic acid,succinic acid, fumaric acid, malic acid, tartaric acid, glutaric acid,glutaconic acid, citric acid, adipic acid, pimelic acid, cyclohexen-1,2diacid, (o, m, or p)-phthalic acid, hydroxyphthalic acid, suberic acid,trimellitic acid, or sebaric acid. The chain length of such a diacid ortriacid may be varied to enhance formation of the fluoride-exchangemetal chelate, and the release of fluoride from the chelate. The variousX groups depicted in the above structures may be the same as, ordifferent from one another, as may the various Y or Z groups. The numbern is an integer from 0 to 16. The preferred n is 6 to 12 in R1 to R3 andthe preferred n is 0 to 4 in R4 through R13.

Preferred multidentate chelating groups L are those containingbis(carboxymethyl)-L-lysine, hydroxypyridinones, catechols, orsubstituted or unsubstituted aromatic β-diketones; and having amolecular weight between 100 and 2000, for example, one of the followingstructures L1-L17:

wherein a dotted line represents the bond between R and a chelatinggroup L; X is either an oxygen or an NH group; Z₁ is hydrogen or analkyl group containing 1 to 4 carbons (e.g., methyl, ethyl, propyl,isopropyl, n-butyl, tert-butyl); Z2 is hydrogen, fluorine, or an alkylgroup containing 1 to 4 carbons (e.g., methyl, ethyl, propyl, isopropyl,n-butyl, tert-butyl); a preferred Z2 is fluorine; m is an integer from 0to 6; a preferred m is 0 or 1.

The synthesis of the R and L groups can be carried out separately or incoordination. The R and L groups can be linked (coupled) through ester,amide, ether, amine, or other covalent bonds; formed, for example, byreactions between activated acid and alcohol or amine, between alkylbromide (or chloride or iodide) and alcohol, or between alkyl bromide(or iodide) and primary or secondary amine. Before the couplingreaction, the “donor” groups on the chelating ligands, such as the —OHor —NOH groups in catechols or hydroxypyridinones, should be protected,for example by forming a methyl or benzyl ether to inhibit unwantedaddition reactions to these groups. After the coupling reaction, theprotection groups are removed, for example by reaction with BBr₃ (toremove a methyl group), or with H₂/Pd or concentrated acid or BCl₃ (toremove a benzyl group).

Below are illustrative examples of methods that may be used for thesynthesis of the R groups, and linking them to the L groups:

-   -   (1) R1 can be synthesized by reaction of methacryloyl chloride        with an aliphatic bromo-1-alcohol containing 2-12 carbons, such        as bromoethanol, 3-bromo-1-propanol, 4-bromo-1-butanol,        6-bromo-1-hexanol, 8-bromo-1-octanol, 10-bromo-1decanol,        1′-bromo-1-undecanol, or 12-bromo-1-dodecanol.    -   (2) R2 can be synthesized by reaction of methacryloyl chloride        with a hydroxyl aliphatic carboxylic acid containing 8-16        carbons, such as 10-hydroxydecanoic acid, 11-hydroxyundecanoic        acid, 12-hydroxyoctadecanoic acid, 15-hydroxypentadecanoic acid,        16-hydroxyhexadecanoic acid, or a long chain aliphatic amino        acid containing 8-16 carbons such as 11-aminoundecanoic acid, or        12-aminododecanoic acid. Then the acid may be activated by        reaction with thionyl dichloride (SOCl₂), oxylyl chloride        (COCl₂), tosyl chloride, dicyclohexylcarbodiimide (DCC) and        N-hydroxysuccinimide (NHS), or 2-mercaptothiazoline.    -   (3) R3 can be synthesized by reaction of methacryloyl chloride        with a p-, m-, or o-hydroxybenzoic acid or with a p-, m-, or        o-aminobenzoic acids, followed by activation as described above.    -   (4) R4 and R5 can be synthesized by the reaction of        benzene-1,3,5-tricarbonyl trichloride with hydroxyl methacrylate        (synthesized with methacryloyl chloride and aliphatic diols such        as 2-hydroxyethyl methacrylate (HEMA)), amino methacrylamide        (synthesized with methacryloyl chloride and aliphatic diamine),        or an amino methacrylate such as 2-aminoethyl methacrylate; and        then activating the remaining acid group.    -   (5) R6 and R7 can be synthesized by reaction of        cyclohexane-1,3,5-tricarbonyl trichloride with hydroxyl        methacrylate (synthesized with methacryloyl chloride and        aliphatic diols such as 2-hydroxyethyl methacrylate (HEMA)),        amino methacrylamide (synthesized with methacryloyl chloride and        aliphatic diamine), or an amino methacrylate such as        2-aminoethyl methacrylate; and then activating the remaining        acid group.    -   (6) R8 can be synthesized by reaction of phthalic dianhydride        with hydroxyl methacrylate (synthesized with methacryloyl        chloride and aliphatic diols such as 2-hydroxyethyl methacrylate        (HEMA)), amino methacrylamide (synthesized with methacryloyl        chloride and aliphatic diamine), or an amino methacrylate such        as 2-aminoethyl methacrylate; and then activating the remaining        acid group.    -   (7) R9, R10, and R12 can be synthesized by first coupling        protected L groups containing a secondary amine to a substituted        or unsubstituted bisphenol, a substituted or unsubstituted        bisphenol, or dihydroxybenzene, through a Manich-type reaction        with formaldehyde, and then reacting with glycidyl methacrylate        or glycidyl methacrylamide, and afterwards removing the        protective groups.    -   (8) R11 can be synthesized by first reacting        4,4-bis(4-hydroxyphenyl)pentanoic acid with glycidyl        methacrylate, or glycidyl methacrylamide, or 2-bromoethyl        methacrylate, or other n-bromoalkyl methacrylate (e.g.,        synthesized by reaction of n-bromoalcohol and methacryloyl        chloride); and then activating the acid group.    -   (9) R13 can be synthesized by first reacting dihydroxy phthalic        acid with glycidyl methacrylate or glycidyl methacrylamide, or        reacting dichlorophthalic acid with n-hydroxyalkyl methacrylate        or n-hydroxyalkyl methacrylamide; and then activating the acid        groups.

Below are illustrative examples of methods that may be used for thesynthesis of the ligand groups L:

-   -   (1) L1 is bis(carboxymethyl)-L-lysine, which is commercially        available.    -   (2) L2 and L6 can be synthesized by first reacting        2,6-dibromopyridine with dihydroxyalkylamine (whose secondary        amine has been linked to an R group), or n-bromoalcohol, and        then reacting with a diamine. The bromopyridine groups are then        oxidized with H₂O₂ to 1,2-HOPO.    -   (3) L3, L9 and L14 can be synthesized by first reacting        3-methoxypyridin-2(1H)-one or 3-benzoxypyridin-2(1H)-one with a        diiodoalkane or a dichloroalkane containing 1 to 5 carbons, or        with an n-iodoalcohol containing 1 to 5 carbons; followed by        chlorination with tosyl chloride; and then reacting with ammonia        or primary amine to form L3, or diamine to form L9 and L13.    -   (4) L4 can be synthesized by first reacting        3-methoxypyridin-2(1H)-one or 3-benzoxypyridin-2(1H)-one with a        dibromo-aliphatic acid such as 3-bromo-2-(bromomethyl)propanoic        acid.    -   (5) L5 can be synthesized by first converting the primary amine        group in dopamine to a bromide, by reacting with NaNO₂ and HBr,        or with a Grignard reagent, and then reacting the bromide with        dopamine.    -   (6) L7, L8, L12, and L13 can be synthesized by first reacting        3-methoxypyridin-2(1H)-one or 3-benzoxypyridin-2(1H)-one with an        iodoalkane containing 1 to 5 carbons to form an        N-alkyl-substituted pyridinone, and then reacting with AlCl₃ or        Br₂ to form 4-chloro-pyridinone or 4-bromo-pyridinone, which in        turn reacts with a dihydroxyl alkylamine (whose secondary amine        has been linked to the an R group) to form L7, or with an        N-bromoalcohol; the products react with a diamine to form L8 and        L12. L13 can be synthesized by addition of the intermediate for        the synthesis of L2 and L6 to L8.    -   (7) L10 can be synthesized by reaction of dopamine with a        dibromoalkane or diiodoalkane.    -   (8) L11 can be synthesized by reaction of        3-methoxypyridin-2(1H)-one or 3-benzoxypyridin-2(1H)-one with a        bis(bromoalkyl)-diol such as        2,2-bis(bromomethyl)propane-1,3-diol.    -   (9) L15 can be synthesized by reaction of dimethyl        5-hydroxyisophthalate with acetone or a substituted acetone such        as 1,1,1-trifluoroacetone.    -   (10) L16 and L17 can be synthesized by first reacting methyl        4-hydroxybenzoate with acetone or a substituted acetone such as        1,1,1-trifluoroacetone, and then reacting with a        bis(bromoalkyl)-diol such as        2,2-bis(bromomethyl)propane-1,3-diol, or a dibromo-aliphatic        acid such as 3-bromo-2-(bromomethyl)propanoic acid.

The preferred fluoride-releasing monomers may be prepared from chelatingmonomers such as those described above and metal fluorides or anionicfluoride complexes (as acids or alkyl ammonium salts, e.g. H₂ZrF₆ or(Bu₄N)₂ZrF₆) that are at least somewhat soluble in a polar organicsolvent such as methanol, DMF, tetraethyleneglycol dimethacrylate,dimethylsulfone (DMSO), or a mixed water-organic solvent. The acidicternary metal fluoride complexes can be converted to the neutral saltsof lithium, sodium, tetraalkyl ammonium or pyridinium by reaction withthe corresponding hydroxides.

An alternative method for preparing the fluoride-releasing monomers isto first react an acidic chelating monomer with a metal salt that ispartially soluble in the organic solvent, e.g., a nitrate or acetate,and then adding fluoride, e.g., as HF, NaF, NH₄F, LiF, or a tetraalkylammonium fluoride such as (CH₃)₄NF, (C₂H₅)₄NF, or [CH₃(CH₂)₃]₄NF.However, the metal ions may also form strong chelates with multiplechelating monomers or even with polymers that are insoluble in organicor aqueous solvents.

Chelating monomers may be generated from combinations of differentpolymerizable groups (e.g., R1-R13). Furthermore, the chelating groupsmay generate many chelating monomers. Examples of suchfluoride-releasing monomers formed from chelating monomers, zirconium,and fluoride include the following:

The chelating monomers and fluoride-releasing monomers may be dissolvedin, or mixed with, monomers or mixtures of monomers or other materialsknown in the art for use in dental materials, such as bisphenol Aglycidyl dimethacrylate, hydroxyl ethyl methacrylate, triethyleneglycoldimethacrylate, and urethane dimethacrylate. The amount of thefluoride-releasing monomers may be from about 0.1% to about 70% byweight of total monomers, depending on the requirements for fluoriderelease and other physical and mechanical properties, the preferredratio being from about 20% to about 40%. The monomer mixtures may bepolymerized (cured) by means known in the art, such as free radicalreactions initiated by photoinitiators or chemical initiators. Suchphotoinitiators include diketones such as camphorquinone, and1-phenyl-1,2-propanedione (PPD). Preferred chemical initiators areorganic peroxides such as benzoyl peroxide. Reducing agents oraccelerators may also be added, such as aliphatic or aromatic tertiaryamines, for example dimethylaminoethyl methacrylate. The total ratio ofinitiators and accelerators is typically between about 0.03% and about5% by weight of total materials, with a preferred range between about0.3% and about 1%.

The chelating monomers containing ligand group L1, fluoride-releasingmonomers and their mixtures can be used in self-etching primers andself-etching dental bonding agents. Their concentration may be from 1%to about 50% by weight of total solution. The self-etching primers anddental bonding agents may contain other dental monomers, photoinitiatorsand solvents.

The chelating monomer, fluoride-releasing monomers and their mixtureswith other monomers may be used with or without fillers. Preferredcompositions for dental composite resins contain both fluoride-releasingmonomers and fluoride-releasing filler particles such as afluoroaluminosilicate glass, for example, that described in U.S. Pat.No. 5,332,429. The fillers may also include other inorganic compoundssuch as SiO₂, ZrO₂, TiO₂, ZrF₄, NaF, AlF₃, LiF, SrF₂, CeF₃, Ca₃(PO₄)₂,La₂O₃, Ce₂O₃ and glasses incorporating these compounds. Preferredparticle sizes for fillers are 0.1 to 5 micrometer, more preferably 0.2to 3 micrometer.

To enhance bonding between the filler and the resin matrix, the fillersurface is preferably treated with a silane coupling agent, such asγ-methacryloyl-oxypropyltrimethoxysilane,γ-mercaptopropyltriethoxysilane, γ-aminopropyltrimethoxysilane, orO-(methacryloxyethyl)-N-(triethoxysilylpropyl)urethane. Alternatively,the filler particles may be treated with an organic acid containing oneor more polymerizable functional groups, including for example one ormore chelating monomers in accordance with the present invention. Thefiller load may vary by type of application: for example, it can rangefrom about 5% to about 50% in a sealant or a filled dental adhesive,from about 40% to about 60% for flowable composites, and up to about 85%for posterior composites.

Applications for the chelating monomers and fluoride-releasing monomersof the present invention include, for example, dental restorativematerials such as composite resins, compomers, resin-modified glassionomers, sealant, liners, cements, provisional/temporary materials,dental adhesives (bonding agents), denture base resins, and orthodonticadhesives.

Alternatively, polymers and composites made from the novel chelatingmonomers and their metal chelates may also be used in the preparation ofion exchange resins, which may be used, for example, in the separationof metals, fluoride ions, and other anions by chemical manufacturers oranalytical laboratories; or in the removal of hazardous metals orunwanted fluoride from industrial waste water. The chelating monomersmay also be used to coat metal surfaces including dental and medicalimplants to enhance protection or bonding.

Examples are given below of several of the synthesis of severalembodiments of chelating monomers in accordance with this invention,namely, certain ternary zirconium fluoride chelates and their use influoride-releasing dental bonding agents.

Reagents and Analyses. Methacryloyl chloride, 10-aminodecanoic acid,N-hydroxysuccinimide (NHS), dicyclohexylcarbodiimide (DCC),N_(α),N_(α)-bis(carboxymethyl)-L-lysine, H₂ZrF₆ (48% solution in H₂O),camphorquinone (CQ), 2-(dimethylamino)ethyl methacrylate (DMAEM), phenylbis(2,4,6-trimethylbenzoyl)phosphine oxide (PO), dimethylformamide(DMF), hydrochloric acid (HCl, 37%), acetic acid, sodium carbonate,tetrahydrofuran (THF), diethyl ether, anhydrous magnesium sulfate(MgSO₄), and ethyl acetate were used as received from Aldrich. Fouriertransform infrared (FTIR) spectra were recorded on a Bio-Rad FTS-40 FTIRspectrometer. NMR spectra were measured by a Bruker AC400 NMRspectrometer, using CDCl₃, CD₃OD or DMSO-d₆ as solvent. ESMS was carriedout on a Bruker Daltonic Esquire 3000 Ion Trap mass spectrometer. Thesample solutions (approx. 10⁻⁴ M) were directly infused via a syringepump (model 74900, ColeParmer) at a flow rate of 240 μl/h. Thenon-fluoride-releasing commercial dental composite Synergy Flow™ and itsresin components (activated, unfilled monomer 12166-KG13™, and silanizedfiller 12204-JE39™) were provided by Coltène Whaledent (Mahwah, N.J.).Fluoride-releasing flowable composites were obtained from IvoclarVivadent (Tetric-Flow™) and Pulpdent (Flows-Rite™). Commercial bondingagents Clearfil SE Bond™ and Clearfil Protect Bond™ were provided byKurarary.

EXAMPLE 1 Synthesis of 11-Methacrylamidoundecanoic Acid

10-Aminodecanoic acid (4.04 g, 20 mmol) was dissolved in 300 ml of THFand water (1:1) in an ice-water bath, and then sodium carbonate (3.18 g,30 mmol) was added. Methacryloyl chloride (3.15 g, 30 mmol) was slowlyadded, and the mixture was stirred for 5 h. After reaction was complete,the solution was neutralized to pH 5 with HCl. Then the solvent wasremoved by evaporation, and the residue was extracted with 200 mlCH₂Cl₂, producing a white solid. Recrystallization from a hexane/ethylacetate solution gave 4.96 g product (yield 92%). Alternatively,replacing THF/H₂O with CHCl₃ gave a similar or higher yield.

Analysis: ¹HNMR (CDCl₃, 400 MHz) δ: 5.69 (s, 1H, CHH═), 5.32 (s, 1H,CHH═), 3.30 (m, 2H, NHCH₂CH₂), 2.34 (t, 2H, J=7.4 Hz, CH₂CH₂COOH), 1.97(s, 3H, CH₂═CHCH₃), 1.48-1.70 (m, 4H, NHCH₂CH₂CH₂ and CH₂CH₂CH₂COOH),1.24-1.38 (m, 12H, NHCH₂CH₂(CH₂)₆CH₂CH₂COOH). ¹³C-NMR (CDCl₃, 400 MHz)δ: 179.50 (COON), 168.86 (CH₂═CCH₃CONHCH₂), 140.26 (CH₂═CCH₃CONHCH₂),119.67 (CH₂═CCH₃), 40.00 (CH₂═CCH₃CONHCH₂CH₂), 34.29 (CH₂CH₂COOH),29.70, 29.57, 29.47, 29.40, 29.35, 29.19, 27.10, 24.90(CH₂═CCH₃CONHCH₂(CH₂)₈CH₂COOH), 18.92 (CH₂═CCH₃). ESMS (THF/H₂O,negative ion): m/z=268.2 ([M−H]⁻, calculated: 268.2).

EXAMPLE 2 Synthesis of2,5-Dioxopyrrolidin-1-yl-11-Methacrylamidoundecanoate (Compound 2)

To a solution of 11-methacrylamidoundecanoic acid (1.35 g, 5 mmol) inethyl acetate/dimethylformamide (50 ml, 1:1) in ice/water bath wereadded solutions of N-hydroxysuccinimide (0.58 g, 5 mmol) and ofdicyclohexylcarbodiimide (DCC, 1.03 g, 5 mmol), each indimethylformamide (10 ml). The resulting mixture was stirred for 2 h inan ice/water bath, and then stirred at room temperature overnight indarkness. Glacial acetic acid (0.05 ml) was then added. After stirringfor 1 h, the solution was filtered, and the solvents were removed,giving the crude product. Recrystallization from an ethanol solutiongave 1.32 g product (yield 72%).

Analysis: ¹H NMR (CD₃OD, 400 MHz) δ: 5.66 (s, 1H, CHH═), 5.35 (s, 1H,CHH═), 3.22 (m, 2H, NHCH₂CH₂), 2.63 (t, 4H, J=6.6 Hz, COCH₂CH₂CO), 2.53(t, 2H, J=6.8 Hz, CH₂CH₂COO), 1.93 (s, 3H, CH₂═CHCH₃), 1.48-1.74 (m, 4H,NHCH₂CH₂CH₂ and CH₂CH₂CH₂COO), 1.28-1.38 (m, 12H,NHCH₂CH₂(CH₂)₆CH₂CH₂COO). ¹³C NMR (CD₃OD, 400 MHz) δ: 171.86(COCH₂CH₂CO), 171.17 (CH₂═CCH₃CONHCH₂), 170.27 (CH₂COO), 141.47(CH₂═CCH₃CONHCH₂), 120.16 (CH₂═CCH₃), 40.66 (CH₂═CCH₃CONHCH₂CH₂), 32.17(CH₂CH₂COO), 30.58, 30.48, 30.41, 30.29, 30.00, 29.77, 28.02, 26.49(CH₂═CCH₃CONHCH₂(CH₂)₈CH₂COO), 25.76 (COCH₂CH₂CO), 18.87 (CH₂═CCH₃).

EXAMPLE 3 Synthesis of chelating monomer R1L1,2,2′-(1-Carboxy-5-(11-methacrylamidoundecanamido)pentylazanediyl)diaceticacid, (Compound 3)

To N_(α),N_(α)-bis(carboxymethyl)-L-lysine (262.1 mg, 1 mmol) in water(10 ml) in an ice/water bath was added2,5-dioxocyclopentyl-1′-methacrylamidoundecanoate (336.2 mg, 1 mmol) in10 ml THF and Na₂CO₃ (106 mg, 1 mmol). The resulting mixture was stirredfor 2 h in an ice/water bath, and then stirred at room temperatureovernight in darkness. After reaction was complete, the solution wasacidified to pH 2. Then the solvent was removed by evaporation, and theresidue was extracted with THF. Recrystallization of the crude productfrom a chloroform/ether solution gave 328.4 mg product (yield 64%).

Analysis: ¹H NMR (DMSO-d₆, 400 MHz) δ: 5.62 (s, 1H, CHH═), 5.29 (s, 1H,CHH═), 3.47 (s, 4H, NH(CH₂)₂CH₂CH₂CH(COOH)N(CH₂COOH)₂), 3.32 (t, 1H,J=7.4 Hz, NHCH₂(CH₂)₃CH(COOH)N(CH₂COOH)₂), 3.08 (m, 2H,NHCH₂(CH₂)₃CH(COOH)N(CH₂COOH)₂), 2.99 (m, 2H, NHCH₂(CH₂)₉CONH), 2.02 (t,2H, J=7.4 Hz, NH(CH₂)₉CH₂CONH), 1.84 (s, 3H, CH₂═CHCH₃), 1.31-1.66 (m,8H, NHCH₂CH₂(CH₂)₈CH₂CH₂CONH and NHCH₂CH₂CH₂CH₂CH(COOH)N(CH₂COOH)₂)),1.18-1.30 (m, 14H, NH(CH₂)₂(CH₂)₆(CH₂)₂CONH andNH(CH₂)₂CH₂CH₂CH(COOH)N(CH₂COOH)₂). ¹³C NMR (DMSO-d₆, 400 MHz) δ: 173.92(NH(CH₂)₄—CH(COOH)N(CH₂COOH)₂), 173.19 (NH(CH₂)₄—CH(COOH)N(CH₂COOH)₂),171.79 (NH(CH₂)₉CH₂CONH), 167.21 (CH₂═CCH₃CONH(CH₂)₉CH₂CONH), 140.03(CH₂═CCH₃CONH(CH₂)₉CH₂CONH), 118.54 (CH₂═CCH₃CONH(CH₂)₉CH₂CONH), 64.19(NH(CH₂)₄—CH(COOH)N(CH₂COOH)₂), 53.28 (NH(CH₂)₄—CH(COOH)N(CH₂COOH)₂),38.75, (CH₂═CCH₃CONHCH₂(CH₂)₉CONH), 38.13(NHCH₂(CH₂)₃CH(COOH)N(CH₂COOH)₂), 35.33 (CH₂═CCH₃CONH(CH₂)₉CH₂CONH),29.23, 28.97, 28.89, 28.82, 28.78, 28.70, 28.68, 28.62, 26.36, 25.23,23.02 (CH₂═CCH₃CONHCH₂(CH₂)₈CH₂COOH and NHCH₂(CH₂)₃CH(COOH)N(CH₂COOH)₂).ESMS (THF/H₂O, negative ion): m/z=512.3 ([M−H]⁻, calculated: 512.2).

EXAMPLE 4 Synthesis of2,2′-(1-Carboxy-5-(11-methacrylamidoundecanamido)pentylazanediyl)diaceticacid zirconium (IV) fluoride complex (Compound 4)

To a solution of2,2′-(1-carboxy-5-(11-methacrylamidoundecanamido)pentylazanediyl)diaceticacid (51.3 mg, 0.1 mmol) in 10 ml THF and water (1:1) was slowly addedH₂ZrF₆ (43.1 mg, 0.1 mmol, 48% solution in H₂O) with stirring at roomtemperature. After 1 h, the mixture was filtered. A colorless oilcomplex was obtained, 70 mg (97.2% yield) after removal of the solvents.ESMS (THF/H₂O, negative ion): m/z=638.2 ([M−H]⁻, calculated: 638.2).

EXAMPLE 5 Synthesis of2,2′-(1-Carboxy-5-(11-methacrylamidoundecanamido)pentylazanediyl)diaceticAcid Zirconium (IV) Fluoride Complex (Compound 5)

To a solution of ZrF₄ (16.7 mg, 0.1 mmol) in 10 ml THF and water (1:1)was added (C₄H₉)₄NF (28.1 mg, 0.1 mmol) with stirring at roomtemperature. After 1 h,2,2′41-carboxy-5-(1′-methacrylamidoundecanamido)pentylazanediyl)diaceticacid (51.3 mg, 0.1 mmol), in 10 ml THF and water (1:1), was slowly addedto the solution with stirring at room temperature. After 1 h, themixture was filtered. Colorless oil complex (Compound 5) was obtained(90 mg, 93.7%) after the solvents were removed. ESMS (THF/H₂O, negativeion): m/z=638.0 ([M-NBu₄]⁻, calculated: 638.1). ESMS positive ion:m/z=242.4 ([NBu₄]⁺, calculated: 242.28)

EXAMPLE 6 Synthesis of 3-(benzyloxy)pyridin-2(1H)-one (6)

KOH (10 g, 180 mmol) was stirred in methanol (260 mL) for 10 minutes,until completely dissolved. Then 2,3-dihydroxypyridone (20 g, 180 mmol)was added to the KOH/methanol solution, which was then stirred foranother 10 minutes. Benzyl chloride (23.6 mL, 200 mmol) was then slowlyadded to the reaction mixture. The reaction mixture was stirred andheated at 40° C. Reaction progress was monitored by ESMS. After 3.5hours, ESMS showed that the starting material 2,3-dihydroxypyridinonehad been almost completely consumed. Then the methanol solvent wasevaporated under vacuum at 40° C. The residue was dissolved with water(100 mL) and extracted 3 times (150 mL) with CH₂Cl₂. The combinedorganic extracts were dried over MgSO₄, filtered, and concentrated invacuo. Recrystallization in ethanol gave 10.14 g (28% yield) of product3-(benzyloxy)pyridin-2(1H)-one (Compound 6). ES-MS (positive ion inMeOH/H₂O): m/z=202.1, ([M+H]⁺ calculated: 202.09).

EXAMPLE 7 Synthesis of 3-(benzyloxy)-1-(3-iodopropyl)pyridin-2(1H)-one(Compound 7)

To a solution of 1,3-diiodopropane (7.1 mL, 63 mmol) in tetrahydrofuran(50 mL) was added 3-(benzyloxy)pyridin-2(1H)-one (1.28 g, 6.3 mmol) andNa₂CO₃ (0.67 g, 6.3 mmol). The mixture was then stirred at 70° C. for 1day. Reaction progress was monitored by ES-MS. After ESMS showedessentially complete consumption of the starting material3-(benzyloxy)pyridin-2(1H)-one, the reaction was stopped. Then thereaction mixture was filtered, concentrated, and subjected to flashcolumn chromatography (eluent: hexane:ethylacetate 1:1). Compound 7 wasobtained (240 mg, 10% yield). Analysis: ES-MS (positive ion inMeOH/H₂O): m/z=370.2, ([M+H]⁺, calculated: 370.03).

EXAMPLE 8 Synthesis of1,1′-(3,3′-(6-hydroxyhexylazanediyl)bis(propane-3,1-diyl))bis(3-benzyloxy)pyridin-2(1H)-one) (Compound 8)

To a solution of 6-amino-hexanol (11.7 mg, 0.1 mmol) in tetrahydrofuran(1 mL) was added 3-(benzyloxy)-1-(3-iodopropyl)pyridin-2(1H)-one (74 mg,0.2 mmol), and Na₂CO₃ (22 mg, 0.2 mmol). The reaction mixture was thenstirred at 70° C. for 1 day. Reaction progress was monitored by ES-MS.After ESMS showed essentially complete consumption of the startingmaterial 3-(benzyloxy)-1-(3-iodopropyl)pyridin-2(1H)-one, the reactionwas stopped. Then the reaction mixture was filtered, concentrated, andwashed with hexane, yielding Compound 8. Analysis: ES-MS (positive ionin MeOH/H₂O): m/z=600.6, ([M+H]⁺, calculated: 600.34).

EXAMPLE 9 Synthesis of6-(bis(3-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)propyl)amino)hexylmethacrylate (Compound 9)

To a mixture of6-(bis(3-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)propyl)amino)hexylmethacrylate (0.05 mmol) in CH₂Cl₂ (2 mL) was added methacryloylchloride (0.06 mmol) at 0° C. The mixture was stirred for 10 minutesunder nitrogen, and then triethylamine (6 μL) was added to the mixturewith stirring. The temperature of the reaction mixture was graduallyincreased to room temperature, and the reaction mixture continued to bestirred for 1 day. The reaction progress was monitored by ES-MS. Afterthe reaction had completed, the solvent mixture was removed at 40° C.under vacuum. A solid product was obtained, Compound 9. The product waspurified by column chromatography. Analysis: ES-MS (positive ion inMeOH/H₂O): m/z=668.7, ([M+H]⁺, calculated: 668.4).

EXAMPLE 10 Synthesis of Chelating MonomerR1L3,6-(bis(3-(3-hydroxy-2-oxopyridin-1(2H)-yl)propyl)amino)hexylmethacrylate (Compound 10)

To a pre-cooled flask was added a mixture of6-(bis(3-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)propyl)amino)hexylmethacrylate (Compound 9) (0.02 mmol) and trichloroboron (1 M in CH₂Cl₂,0.1 mL) at 0° C. The mixture was stirred under nitrogen for 2 hours, asthe temperature was gradually increased from 0° C. to room temperature.Reaction progress was monitored by ES-MS. After ESMS showed essentiallycomplete consumption of the starting material6-(bis(3-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)propyl)amino)hexylmethacrylate, the reaction was stopped. Then methanol (2 mL) was slowlyadded to the reaction mixture with stirring for 10 minutes to react withthe excess trichloroboron. The solvent was then removed at 40° C. undervacuum to give the solid product Compound 10. The product was purifiedby column chromatography. Analysis: ES-MS (positive ion in MeOH/H₂O):m/z=488.5, ([M+H]⁺, calculated: 488.3).

EXAMPLE 11 Synthesis of6-{bis[3-(3-hydroxy-2-oxo-1,2-dihydropyridin-1-yl) propyl]amino}hexylmethacrylate zirconium (IV) fluoride complex (Compound 11)

To a solution of Compound 10 (0.01 mmol) in MeOH (0.2 mL) was slowlyadded H₂ZrF₆ (4.5 wt % solution in water, 45 μL, 0.01 mmol) withstirring at room temperature. After 30 minutes, the solvent wasevaporated, and Compound 11 was obtained as a white solid. ES-MS(negative ion in MeOH/H₂O): m/z=632.3, ([M−H]⁻, calculated: 632.15). TheES-MS spectra at different pH values (4-9) indicated that complex 11 cansurvive at pH=7.5 (MeOH/H₂O, 70/30), which is of clinical importancesince normal physiological pH is ˜7.2-7.4.

The following examples demonstrate an alternative method to synthesizechelating monomers containing 3,2-HOPO groups. This method offers highyield and easily purified products, with minimal formation of unwantedby-products.

EXAMPLE 12 Synthesis of3-(benzyloxy)-1-(3-hydroxypropyl)pyridin-2(1H)-one (Compound 12)

To the solution of Compound 6 (0.202 g, 1 mmol) in acetonitrile wasadded K₂CO₃ (2 equiv.) followed by iodopropanol (0.186 g, 1 mmol). Thereaction mixture was stirred at 65° C. overnight. On completion of thereaction, the reaction mixture was filtered and solvent was evaporatedunder vacuum. The residue was dissolved in water and extracted threetimes with CH₂Cl₂. The combined organic extracts were dried over Na₂SO₄,filtered, and concentrated in vacuum. The resulting compound 12 waspurified by column chromatography (2:100, CH₃OH/CH₂Cl₂). Yield: (85%)

Analysis: ¹HNMR: δ 1.9 (m, 2H, —N—CH₂—CH₂—CH₂—OH), δ 3.25 (br, 1H, —OH),δ 3.5 (m, 2H, —N—CH₂—CH₂—CH₂—OH) δ 4.19 (m, 2H, —CH₂—OH), δ 5.1 (m, 2H,Ph-O—CH₂-Ph) δ 6.15 (m, 1H, Ph), δ 6.7 (m, 1H, Ph) δ 6.95 (m, 1H, Ph) δ7.3-7.5 (m, 5H, Ph). ES-MS (positive ion, in methanol); m/z=260.0 ([M]⁺,calculated: 260.12).

EXAMPLE 13 Synthesis of3-(benzyloxy)-1-(3-chloropropyl)pyridin-2(1H)-one (Compound 13)

Triethylamine (3 mmol) followed by tosyl chloride (1.25 mmol) were addedto a stirred solution of 12 (1 mmol) in dry CH₂Cl₂ at room temperature.The reaction mixture was stirred overnight, diluted with CH₂Cl₂ (100ml), and washed with 5% NaHCO₃ (3×50 ml) and brine (1×50 ml). Theorganic solution was dried over Na₂SO₄ and concentrated in vacuo. Theyellow oil was purified by flash chromatography (cyclohexane:AcOEt70:30) to give Compound 13 in 86% yield.

Analysis: ¹H-NMR: δ 2.3 (m, 2H, —N—CH₂—CH₂—CH₂—Cl), δ 3.5 (m, 2H,—N—CH₂—CH₂—CH₂—OH), δ 4.2 (m, 2H, —N—CH₂—CH₂—CH₂—OH), δ 5.1 (m, 2H,Ph-O—CH₂-Ph), δ 6.05 (m, 1H, Ph) δ 6.7 (m, 1H, Ph) 6.95 (m, 1H, Ph) δ7.3-7.5 (m, 5H, Ph). ES-MS (positive ion, in methanol); m/z=278.3 ([M]⁺,calculated: 278.09).

EXAMPLE 14 Synthesis of1,1′-(3,3′-azanediylbis(propane-3,1-diyl))bis(3-(benzyloxy)pyridin-2(1H)-one)(Compound 14)

A solution of 7M ammonia in methanol (3.12 mL) was added to 1.0 mmol ofcompound 13 (dissolved in 2 mL of methanol) in a sealed 10 mLmicrowavable vial. The reaction mixture was heated with stirring at 130°C. in a MARS microwave reaction system (CEM Corporation) for 2 hours.The solvent was evaporated under vacuum to obtain the product 14.Analysis: ES-MS (positive ion, in methanol); m/z=500.7 ([M+K]⁺,calculated: 500.25).

EXAMPLE 15 Synthesis of4,4-bis(4-(2-(methacryloyloxy)ethoxy)phenyl)pentanoic acid (Compound 15)

A mixture of compound 4 (1 mmol), K₂CO₃ (2 mmol) in 2 ml of acetone wasadded to a solution of 2-bromomethacrylate (2.2 mmol) in 2 ml acetone.The mixture was stirred with reflux. After the completion of reaction(12 h to 24 h), the acetone solvent was evaporated from the reactionmixture, and the white residue was re-dissolved in methanol. Followingevaporation of the methanol, a white solid product remained.

Analysis: ¹HNMR: δ 1.42 (s, 3H, (Ph)₂(CH₂)—C—CH₃), δ 1.93 (m, 6H,—OOC—C(CH₃)═CH₂), δ 1.85-2.00 (m, 2H, CH₂—CH₂—COOH), δ 2.15-2.25 (m, 2H,CH₂—CH₂—COOH) δ 4.1-4.2 (m, 4H, Ph-O—CH₂—CH₂—O—CO), δ 4.2-4.3 (m, 2H,Ph-O—CH₂—CH₂-0-00), δ 5.6-5.7 (m, 2H, —C═CH₂) δ 5.9-6.0 (m, 2H, —C═CH₂)δ 6.5-6.65 (m, 4H, Ph) δ 6.8-6.9 (m, 4H, Ph). ES-MS (positive ion, inmethanol); m/z=549.1 ([M+K]⁺, calculated: 549.19); (negative ion, inmethanol); m/z=509.1 ([M−H]⁻, calculated: 509.23).

EXAMPLE 16 Synthesis of2,2′-(4,4′-(5-(bis(3-(3-(benzyloxy)-2-oxopyridin-1(2H)-yl)propyl)amino)-5-oxopentane-2,2-diyl)bis(4,1-phenylene))bis(oxy)bis(ethane-2,1-diyl)bis(2-methylacrylate)(Compound 16)

To a stirred suspension of 1-methyl-2-chloropyridiniumiodide (0.613 g,2.4 mmol) in 1,4-dioxane (10 ml) were added compound 15 (2 mmol) andtriethyl amine (0.486 g, 4.8 mmol) at room temperature. After dropwiseaddition of a solution of compound 14 (2.6 mmol) in 1,4-dioxane (5 ml),the mixture was stirred for about 24 h at 70° C., and was monitored byESMS. The mixture was filtered, and the 1,4-dioxane solvent wasevaporated. The residue was taken up in dichloromethane (50 mL). Thatsolution was washed with 0.5 N aqueous HCL solution, (4×50 mL) and brine(3×50 mL). The collected organic layer was dried over sodium sulfate andevaporated, and the residue was then purified by flash chromatography byelution with dichloromethane:methanol 98:2 (v/v) to give white solidcompound 16.

Analysis: ES-MS (positive ion, in methanol): m/z=992.3, ([M+H]⁺,calculated 992.46).

EXAMPLE 17 Synthesis of Chelating Monomer R11L3 (Compound 17)

To a stirred solution of compound 16 (2 mmol) in dichloromethane (5 mL),BCl₃ (5 ml, 5 mmol) was added slowly at 0° C. The mixture was thenstirred at room temperature for 1.5 hours, and was monitored by ES-MS.The reaction mixture was filtered and diluted with dichloromethane (50mL); washed with 5% NaHCO₃ (3×50 ml) and brine (1×50 ml). The collectedorganic layer was dried over sodium sulfate. The solvent was evaporatedunder vacuum, and the residue (compound 17) was purified by flashchromatography.

Analysis: ES-MS (negative ion, in methanol): m/z=810.2 ([M−H]⁻,calculated: 810.37).

EXAMPLE 18 Synthesis of Zirconium (IV) Fluoride Complex(Fluoride-Releasing Monomer) R11L3-ZrF3H (Compound 18)

To a solution of Compound 17 (0.02 mmol) in MeOH (0.5 mL) was addedH₂ZrF₆ (4.5 wt % solution in water, 90 μL, 0.02 mmol) with stirring atroom temperature. After 20 minutes, the solvent was evaporated, andCompound 18 was obtained as a white solid. Analysis: ES-MS (negative ionin MeOH/H₂O): m/z=956.2, ([M−H]⁻, calculated: 956.26), 936.1 ([M−H−H]⁻,calculated 936.26).

EXAMPLE 19 Fabrication, Photopolymerization, Fluoride Release, FluorideRecharge, and Microtensile Bonding Strength of a Prototype Self-EtchingPrimer, and a Prototype Bonding Agent

An experimental bonding agent (Exp. Bond.) comprising two separatebottles of reagents was formulated as follows: Bottle A. Self-etchingprimer: To a mixture of synthesized monomer 3 (30 wt %), HEMA (30 wt %),acetone (30 wt %) and water (20 wt %) were added camphorquinone (0.02 wt% of the monomer), 1-phenyl-1,2-propane-dione (0.015 wt % of themonomer) and phenyl-bis(2,4,6-trimethylbenzoyl)phosphine oxide (PO)(0.015 wt % of the monomer).

Bottle B. Adhesive bonding agent: To a mixture of synthesized monomer 4(30 wt %), HEMA (30 wt %), Bis-GMA (30 wt %) and UEDMA (10 wt %) wereadded camphorquinone (0.02 wt % of the monomer),1-phenyl-1,2-propane-dione (0.015 wt % of the monomer) andphenyl-bis(2,4,6-trimethylbenzoyl)phosphine oxide (PO) (0.015 wt % ofthe monomer).

Two commercially-purchased bonding agents, which will be calledControl-1 and Control-2, were also tested for comparison.

An experimental composite for testing fluoride-release was formulatedusing 70 wt % fluoroaluminosilicate filler (1.3 μm, Caulk/Dentsply) and30 wt % monomer (BisGMA:EBPADMA:HDDMA 2:2:1). Disk specimens (d5×2 mm,n=5×8) were fabricated, coated with a bonding adhesive on the topsurface, and light-cured for 20 sec. Other surfaces of the disk werecoated with nail polish. The specimen was then immersed in 2 mldeionized water. Fluoride concentration was measured daily for 14 daysusing a fluoride ion-selective electrode. Then the specimens wererecharged by applying “60 Seconds Taste Gel™,” a topical fluoride agent(containing 1.23% w/w fluoride ion) for 1 min and rinsing with runningdeionized water for 1 min. Fluoride release from the recharged sampleswas measured daily for 4 days, and the recharge cycles were repeatedthree times. Microtensile bond strengths (MTBS) of the three bondingagents on ground enamel or dentin from extracted human teeth were testedon bar specimens (1×1 mm cross-section, n=10) after 24 h storage indistilled water at 37° C. The data were analyzed using ANOVA and posthoc tests. The results are shown in Table 1.

TABLE 1 Fluoride Release, Recharge, and Microtensile Bonding Strength(MTBS) of Experimental and Commercial Bonding Agents^(a) (Mean ± SD)Experimental Property Bond Control-1 Control-2 Cumulative F-release 46.7± 7.3 0.66 ± 0.22 5.30 ± 2.5 over 14 days (μg/cm²) Cumulative F-release 16.8 ± 12.6 2.12 ± 0.8  2.96 ± 1.9 3 days after recharge (μg/cm²) MTBSon enamel (MPa) 23.7 ± 6.4 20.8 ± 5.97 16.4 ± 2.9 MTBS on dentin (MPa)31.4 ± 6.7 34.2 ± 10.2  53.7 ± 11.6 ^(a)Self-etching primer contained 30wt % monomer 3; bonding agent contained 30 wt % chelate 5.

As shown in Table 1, the experimental bonding agent providedsubstantially higher fluoride release and fluoride recharge (p<0.05). Atthe same time, its bonding strength on both enamel and dentin wassimilar to that of Control-1, which is one of the leading self-etchingdental bonding agents currently on the market.

The complete disclosures of all references cited in this specificationare hereby incorporated by reference. Also incorporated by reference arethe entire disclosures of the following: (1) X. Xu, et al., “Synthesisof new fluoride-releasing dental monomer containing1,2-hydroxypyridinones and zirconium fluoride complexes,” PolymerPreprints (Proceedings of 231st ACS National Meeting, Atlanta, Ga., Mar.26-30, 2006) 2006, 47(1), 337-338. (2) X. Xu, et al., “Synthesis Of NewChelating Monomers Containing Bis(Carboxymethyl)-L-Lysine and TheirZirconium Fluoride Complexes,” Polymer Preprints (Proceedings of 231stACS National Meeting, Atlanta, Ga., Mar. 26-30, 2006) 2006, 47(1),335-336. (3) X. Xu, et al., “Synthesis of new fluoride-releasing dentalmonomer containing 1,2-hydroxypyridinones and zirconium fluoridecomplexes,” Abstract, 231st ACS National Meeting, Atlanta, Ga., Mar.26-30, 2006. (4) X. Xu, et al., “Synthesis Of New Chelating MonomersContaining Bis(Carboxymethyl)-L-Lysine and Their Zirconium FluorideComplexes,” Abstract, 231st ACS National Meeting, Atlanta, Ga., Mar.26-30, 2006.

What is claimed:
 1. A compound having the structure(R)_(i)(L)_(j) or (R)_(i)(L)_(j)(M)_(k)(F)_(l)(N(R′)_(p))_(q) or(R)_(i)(L)_(j)(M)_(k)(F)_(l)(W)_(q) wherein R is selected from the groupconsisting of the following structures R1, R3, R5 to R10, R12, and R13:

and wherein L is selected from the group consisting of the followingstructures L1 to L3, L5 to L10, and L12 to L15:

wherein: M is a metal atom having a valence of +2 or greater; i is aninteger from 1 to 4; j is an integer from 1 to 4; k is an integer from 1to 4; l is an integer from 1 to 4; F is one or more fluoride atoms; N isa nitrogen atom; W or N(R′)_(p) is a counter-ion that maintains theneutrality of the compound; wherein W is selected from the groupconsisting of hydrogen, an alkali metal ion, and ammonium; and whereinN(R′)_(p) is selected from the group consisting of C₁ to C₅₀ substitutedor unsubstituted quaternary ammonium ions, and C₁ to C₅₀ substituted orunsubstituted pyridinium ions; each R′ is a substituted or unsubstitutedaliphatic or aromatic group comprising 1 to 50 carbon atoms, wherein atleast one of the R′ groups comprises at least one polymerizable group;and wherein the various R′ groups can be the same or different; andwherein p is an integer from 1 to 4; q is an integer from 0 to
 4. adotted line represents the position of a bond between R and L; X is anether —O-linkage or an —NH-linkage; and the various X moieties may bethe same or different; Y is hydrogen; or a hydroxyl group; or a halfester of a diacid or triacid selected from the group consisting ofphosphoric acid, oxalic acid, malonic acid, maleic acid, a disubstitutedmaleic acid, succinic acid, fumaric acid, malic acid, tartaric acid,glutaric acid, glutaconic acid, adipic acid, pimelic acid,cyclohexen-1,2-diacid, (o, m, or p)-phthalic acid, citric acid,hydroxyphthalic acid, suberic acid, trimellitic acid, and sebaric acid;or wherein Y is a salt of such a diacid or triacid; and the various Ymoieties may be the same or different; Z is hydrogen or a substituted orunsubstituted alkyl group comprising 1 to 12 carbon atoms; Z₁ ishydrogen or a substituted or unsubstituted alkyl group comprising 1 to 4carbon atoms; and the various Z₁ moieties may be the same or different;Z₂ is hydrogen, fluoride, or a substituted or unsubstituted alkyl groupcomprising 1 to 4 carbon atoms; and the various Z₂ moieties may be thesame or different; n is an integer from 0 to 6; and the various valuesfor the parameter n may be the same or different; and m is an integerfrom 0 to 6; and the various values for the parameter m may be the sameor different.
 2. A compound as recited in claim 1, wherein M is selectedfrom the group consisting of Sn, Zn, Sr, Al, La, Sb, Yb, Ti, Zr, Ce, andTh.
 3. A compound as recited in claim 1, wherein M comprises Zr⁺⁴.
 4. Acompound as recited in claim 1, wherein M comprises Zr⁺⁴, and whereinone or more fluoride ions is coordinated to said Zr⁺⁴.
 5. A compound asrecited in claim 1, wherein one or more fluoride ions is coordinated tosaid M.
 6. A compound as recited in claim 1, wherein said compound hasthe structure (R)_(i)(L)_(j)(M)_(k)(F)_(l)(N(R′)_(p))_(q); wherein atleast one R′ moiety is selected from the group consisting of C₈ to C₂₄substituted or unsubstituted alkyl groups; and wherein at least two R′moieties are each selected from the group consisting of substituted orunsubstituted methyl and ethyl groups.